Autotaxin (ATX) was isolated from a culture supernatant of human malignant melanoma cell line A2058 and identified as a cell migration stimulating factor. ATX is also called secreted lysophospholipase D (lysophopholipase D; lysoPLD) and ENPP2 (Ectonucleotide Pyrophosphatase/Phosphodiesterase 2), and mainly affords lysoPLD activity. It hydrolyzes lysophosphatidylcholine (LPC) and produces lysophosphatidic acid (LPA) which is a lipid mediator having various physiological activities.
LPA produced by ATX binds to a G-protein-coupled receptor and intracellularly transmits signals, whereby various physiological actions are shown. As LPA receptor, 6 kinds of subtypes of from LPA1 to LPA6 are known. LPA receptor subtypes are distributed everywhere in the body, at different tissues to be localized in depending on the subtypes, and various receptor subtypes are involved in respective biological functions depending on the tissue. LPA receptor is classified into two subfamilies. LPA1 to LPA3 are classified into the endothelial differentiation gene (Edg) family. LPA4 to LPA6 are non-Edg family LPA receptors, and are receptors similar to the purinergic receptor family (non-patent documents 1 and 2). LPA is physiologically (both homeostasis maintenance and pathology) involved in a wide variety of life phenomena via these LPA receptors. As the actions of LPA via LPA receptors, various functions such as cell proliferation, anti-apoptotic action, cell migration, cancer cell infiltration, wound therapy, development and differentiation of brain nerve system, angiogenesis in fetus, lymphocyte trafficking via high expression of ATX in high endothelial venules (HEVs) and secondary lymphoid tissues, hair follicle formation, bone calcification and the like are known.
On the other hand, firstly in relation to diseases, various studies have revealed that the intracellular signal pathway via ATX and LPA receptor is deeply involved in cancer (non-patent document 3).
In addition, it has been clarified that the intracellular signal pathway via ATX and LPA receptors is involved in various carcinomas and various inflammatory diseases. Specifically, it is related to various diseases including cancer, tumor, neoplasm, various carcinomas such as malignant melanoma, brain tumor, neuroblastoma, glioblastoma multiforme, EBV positive Hodgkin lymphoma, glioblastoma, non-small cell lung cancer, lung tumor, breast tumor, ovary tumor, pancreas tumor, prostatic intraepithelial neoplasia, prostate tumor, thyroid tumor, follicular lymphoma, liver tumor, renal cell carcinoma and the like, asthma, pulmonary fibrosis including idiopathic pulmonary fibrosis, rheumatoid arthritis, type II diabetes-related obesity, atherosclerosis, acute coronary syndrome, hepatic fibrosis, cholestatic pruritus, inflammatory bowel disease, Crohn's disease, ulcerative colitis, neuropathic pain and the like (non-patent document 4).
Furthermore, it has been clarified that intracellular signal pathway via ATX and LPA receptor is involved in various fibrosis diseases.
To be more specific in relation to the involvement in the above-mentioned diseases, for example, it is shown as regards pulmonary fibrosis that LPA concentration increases in alveolar lavage fluid of idiopathic pulmonary fibrosis patients and ATX concentration increases in lung tissue of bleomycin-induced pulmonary fibrosis model. Furthermore, it is shown that progression of bleomycin-induced pulmonary fibrosis and death were markedly suppressed in LPA1 deficient mouse (non-patent documents 5 and 6).
In hepatic fibrosis, it is shown that LPA promotes contraction and growth of hepatic stellate cells that play a key role in hepatic fibrosis, thus suppressing apoptosis, and serum autotaxin activity and plasma LPA level are promoted along with the progression of hepatic fibrosis in chronic hepatitis C patients (non-patent documents 7-9).
In renal fibrosis, it is shown that production of LPA and expression of LPA1 are promoted in a lateral ureteral ligation model, LPA1 deficient mouse shows resistance to fibrosis, and LPA receptor antagonists suppress progression of fibrosis (non-patent document 10).
In neuropathic pain, it has been clarified that LPA produced by ATX contributes to the expression of neuropathic pain, and LPA1 deficient mouse shows resistance to neuropathic pain (non-patent documents 11 and 12).
In rheumatoid arthritis, it has been clarified that the amount of ATX in the synovial tissues and synovial fluids increases in rheumatoid arthritis patients, and ATX conditional knockout mouse shows resistance to the onset of arthritis (non-patent document 13).
In atherosclerosis, LPA accumulates in arteriosclerosis lesions and promotes activation of platelets and endothelial cells by oxidation of low density lipoprotein (non-patent document 14). LPA and ATX accelerate Chemokine (C—X—C motif) ligand 1 production of vascular endothelial cells and promote migration of monocytes (non-patent document 15). Therefore, LPA and ATX are considered to be involved in cardiovascular diseases.
As ATX inhibitors, non-patent document 16 describes a particular lipid analog, patent document 1 describes a tetrahydrocarboline derivative, patent document 2 describes a 1H-indole compound, patent document 3 describes a piperidine or piperazine derivative, and patent document 4 describes a pyridazine derivative.
However, the compound of the present invention is not structurally similar to the compounds described in these patents.
On the other hand, as a compound similar to the compound of the present invention, patent document 5 describes a certain kind of amino-pyrimidine compound, patent document 6 describes a particular aminopyridazine compound, patent document 7 describes a certain kind of amino-pyridine or amino-triazine compound, and patent document 8 describes a certain kind of aminopyridine compound.
However, none of the above-mentioned patent documents describe that the compounds described therein have an inhibitory action on autotaxin and the like.